Abstract
Eleven patients responding successfully to first-line antiretroviral therapy (ART) were investigated for proviral drug resistance mutations (DRMs) in RT by ultra-deep pyrosequencing (UDPS). After molecular typing of the class I alleles A and B, the CTL epitopes in the Gag, Nef and Pol regions of the provirus were sequenced and compared to the reference HXB2 HIV-1 epitopes. They were then matched with the HLA alleles with determination of theoretical affinity (TA). For 3 patients, the results could be compared with an RNA sample of the circulating virus at initiation of therapy. Five out of 11 patients exhibited DRMs by UDPS. The issue is whether a therapeutic switch is relevant in these patients by taking into account the identity of the archived resistance mutations. When the archived CTL epitopes were determined on the basis of the HLA alleles, different patterns were observed. Some epitopes were identical to those reported for the reference with the same TA, while others were mutated with a decrease in TA. In 2 cases, an epitope was observed as a combination of subpopulations at entry and was retrieved as a single population with lower TA at success. With regard to immunological stimulation and given the variability of the archived CTL epitopes, we propose a new concept of curative vaccine based on identification of HIV-1 CTL epitopes after prior sequencing of proviral DNA and matching with HLA class I alleles.
Highlights
HIV-1 infection is a chronic infection with non-stop viral replication leading to a decrease in the number of TCD4 lymphocytes and immunodepression
Are there any resistance mutations to the drugs in proviral DNA, despite the widely held belief that antiretroviral treatment (ART) is fully successful? Second, by taking into account their HLA I alleles, can the archived viral CTL epitopes be presented to the immunological system of these patients, assuming that replication and release from the archived virus constitute a major part of the emerging viral replication at failure or interruption of ART?
ultra-deep pyrosequencing (UDPS) analysis of the epitope demonstrated high stability of both epitopes at baseline and at success within the subspecies (Figure 1). In most of these patients fully responding to first-line ART and with a viral load below the VL threshold and no blip, the proviral DNA load was less than 1000 copies/million PBMC
Summary
HIV-1 infection is a chronic infection with non-stop viral replication leading to a decrease in the number of TCD4 lymphocytes and immunodepression. Antiretroviral treatment (ART) cannot be stopped even in fully responding patients since various clinical trials have shown that its interruption is followed by the resumption of viral replication. In these patients responding successfully to ART, the step is viral eradication, otherwise termed viral cure. We investigated HIV-1 infected patients responding successfully to a first-line ART since they are the main target population for attempts at viral cure. These patients are not extensively investigated on a routine basis since they have an undetectable VL. Are there any resistance mutations to the drugs in proviral DNA, despite the widely held belief that ART is fully successful? Second, by taking into account their HLA I alleles, can the archived viral CTL epitopes be presented to the immunological system of these patients, assuming that replication and release from the archived virus constitute a major part of the emerging viral replication at failure or interruption of ART?
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